Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by the expansion of an unstable CAG repeat located within a novel gene located on the short arm of human chromosome 6. Isolation of the gene affected by SCA1 and characterization of the molecular basis of disease raises several questions regarding the function of the protein, ataxin-1, encoded by the SCA1 gene and how the expansion of a polyglutamine tract within this protein leads to the degeneration of a specific set of neurons within the central nervous system. In addition, important questions remain regarding the mechanism by which a stable, unaffected allele of SCA1 becomes an expanded, affected allele. We and others have proposed that the expansion of the polyglutamine tract of SCA1 into the affected size range in a 'gain in function' mutation such that the ataxin-1 protein assumes a new function which most likely involves a novel interaction with a cellular protein. The experiments proposed in this request for continued support will use the yeast-based genetic assay, the two-hybrid system, to examine protein-protein interactions involving both wild-type and affected alleles of ataxin-1. To examine mechanisms critical for repeat instability, we propose to determine if an expanded CAG repeat tract in transgenic mice established using large YACs from the SCA1 locus are subject to intergenerational instability in repeat number. These latter studies are aimed at determining if cis-acting chromosomal are critical for CAG repeat instability. In summary, the goal of this work is a further understanding of the pathogenesis of CAG repeat based disease and mechanisms important for repeat instability. If successful, this studies will have important implications for SCA1 and, possibly, the other CAG repeat based neurodegenerative disorders.